Low expression of aging-related NRXN3 is associated with Alzheimer disease

Zheng, Junrong; Li, Wen‐Xing; Liu, Jia‐Qian; Guo, Yicheng; Wang, Qian; Li, Gong‐Hua; Dai, Shao‐Xing; Huang, Jing‐Fei

doi:10.1097/md.0000000000011343

Cited by 36 publications

(30 citation statements)

References 42 publications

(45 reference statements)

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“…Interestingly, NRXN3 gene expression is significantly decreased and has the second-highest DEG in AD patients. Moreover, in the hippocampus, NRXN3 gene expression is decreased in both AD- and aging-related groups (Zheng et al, 2018 ). Similarly, we have reported that synaptosome fractions of J20 mice [Alzheimer’s model mice overproducing Aβ (Mucke et al, 2000 )] have a significant reduction in β-NRXs as well as a reduction trend in α-NRXs, compared to their wild-type littermates (Naito et al, 2017b ).…”

Section: Aβ-sensitive Synaptic Organizers In Admentioning

confidence: 99%

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Lee

Khaled

Chofflet

et al. 2020

Front. Cell. Neurosci.

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Synaptic pathology is one of the major hallmarks observed from the early stage of Alzheimer’s disease (AD), leading to cognitive and memory impairment characteristic of AD patients. Synaptic connectivity and specificity are regulated by multiple trans-bindings between pre- and post-synaptic organizers, the complex of which exerts synaptogenic activity. Neurexins (NRXs) and Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are the major presynaptic organizers promoting synaptogenesis through their distinct binding to a wide array of postsynaptic organizers. Recent studies have shown that amyloid-β oligomers (AβOs), a major detrimental molecule in AD, interact with NRXs and neuroligin-1, an NRX-binding postsynaptic organizer, to cause synaptic impairment. On the other hand, LAR-RPTPs and their postsynaptic binding partners have no interaction with AβOs, and their synaptogenic activity is maintained even in the presence of AβOs. Here, we review the current evidence regarding the involvement of synaptic organizers in AD, with a focus on Aβ synaptic pathology, to propose a new classification where NRX-based and LAR-RPTP-based synaptic organizing complexes are classified into Aβ-sensitive and Aβ-insensitive synaptic organizers, respectively. We further discuss how their different Aβ sensitivity is involved in Aβ vulnerability and tolerance of synapses for exploring potential therapeutic approaches for AD.

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Section: Aβ-sensitive Synaptic Organizers In Admentioning

confidence: 99%

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Lee

Khaled

Chofflet

et al. 2020

Front. Cell. Neurosci.

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“…Zheng et al applied the combined p-value method from the R package metaMA to conduct a meta-analysis on three public data sets on AD from the hippocampus and compared their results with those of a data set on normal aging [89]. They found 6205 DEGs for the AD metaanalysis, of which 1291 were also found for normal aging.…”

Section: Comparison With Other Meta-analyses On Pd and Admentioning

confidence: 99%

Comparative transcriptome analysis of Parkinson’s disease and Hutchinson-Gilford progeria syndrome reveals shared susceptible cellular network processes

Hendrickx

Glaab

2020

BMC Med Genomics

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Background: Parkinson's Disease (PD) and Hutchinson-Gilford Progeria Syndrome (HGPS) are two heterogeneous disorders, which both display molecular and clinical alterations associated with the aging process. However, similarities and differences between molecular changes in these two disorders have not yet been investigated systematically at the level of individual biomolecules and shared molecular network alterations. Methods: Here, we perform a comparative meta-analysis and network analysis of human transcriptomics data from case-control studies for both diseases to investigate common susceptibility genes and sub-networks in PD and HGPS. Alzheimer's disease (AD) and primary melanoma (PM) were included as controls to confirm that the identified overlapping susceptibility genes for PD and HGPS are non-generic. Results: We find statistically significant, overlapping genes and cellular processes with significant alterations in both diseases. Interestingly, the majority of these shared affected genes display changes with opposite directionality, indicating that shared susceptible cellular processes undergo different mechanistic changes in PD and HGPS. A complementary regulatory network analysis also reveals that the altered genes in PD and HGPS both contain targets controlled by the upstream regulator CDC5L. Conclusions: Overall, our analyses reveal a significant overlap of affected cellular processes and molecular sub-networks in PD and HGPS, including changes in aging-related processes that may reflect key susceptibility factors associated with age-related risk for PD.

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“…NRXN3 is involved in synaptic function in the cognitive decline associated with aging and AD. Moreover, mutations in NRXN3 have been identified in AD patients ( Zheng et al, 2018 ; Hishimoto et al, 2019 ), and rare deletions have been associated with ASD ( Vaags et al, 2012 ).…”

Section: Genes Associated With Obesity and Neurodegenerative And Neurmentioning

confidence: 99%

“…Interestingly, some genes associated with obesity were also associated with AD by different genetic approaches: candidate gene approach FTO ( Li et al, 2018 ), by differentially expressed genes NRXN3 ( Zheng et al, 2018 ; Hishimoto et al, 2019 ), NPC1 ( Rouillard et al, 2016 ), NEGR1 ( Wray et al, 2018 ), or by GWAS approach: LEPR , BDNF , TNF α, and MTCH2 ( Gao et al, 2015 ; Karch et al, 2016 ; Lemche, 2018 ).…”

Section: Genes Associated With Obesity and Neurodegenerative And Neurmentioning

confidence: 99%

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

2020

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Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin–melanocortin pathway ( LEP , LEPR , POMC , BDNF , MC4R , PCSK1 , SIM1 , BDNF , TrkB , etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity ( FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2 , among others) and with neurodegenerative or neurodevelopmental diseases ( APOE, CD38, SIRT1, TNF α, PAI-1, TREM2, SYT4, FMR1, TET3 , among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene–environment would lead to a better understanding of the etiology of these diseases.

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Low expression of aging-related NRXN3 is associated with Alzheimer disease

Abstract: Supplemental Digital Content is available in the text

Cited by 36 publications

References 42 publications

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity

Comparative transcriptome analysis of Parkinson’s disease and Hutchinson-Gilford progeria syndrome reveals shared susceptible cellular network processes

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

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